The complications of diabetes mellitus continue to be a major source of morbidity and early mortality but have not yet been comprehensively studied from an epidemiological viewpoint. The prevalence, incidence and interrelationships between seven major complication states (i.e., death, proliferative retinopathy, microalbuminuria, overt nephropathy, renal failure, neuropathy, and coronary and lower extremity arterial disease of insulin-dependent diabetes mellitus (IDDM) and their risk factors are being examined in a ten-year prospective study of IDDM subjects diagnosed in childhood. Risk factors and complication status are determined on a biennial basis. The study population is a well-defined cohort of IDDM patients identified from the Children's Hospital of Pittsburgh IDDM Registry shown to be representative of the local county wide diabetic population. The prevalence and four-year incidence rates of these complications have been determined at baseline exam (1986-88) in this cohort of 658 IDDM participants diagnosed between 1/1/50 and 5/31/80. At baseline, they were aged 8-48 years and had a duration of diabetes spanning from 8 to 37 years. Six-year follow-up examinations are currently in progress. In the proposed study period, a further two cycles of biennial exams will be completed using the same methodology for complication endpoints: retinopathy (stereo fundus photography), nephropathy (AER from three timed urine samples), neuropathy (DCCT protocol), peripheral vascular disease (ankle/arm blood pressure ratios at rest), cardiovascular disease (validated MI or angina). In addition to general risk factors (e.g., HbA1, lipids, blood pressure, behavioral risk factors (including smoking, alcohol, and physical activity), new factors will be measured in the proposed grant period including LDL particle size, advanced glycosylated endproduct modified-LDL and oxidized LDL. These new assays are a result of findings to date which suggest a strong lipid-renal connection. Similarly, the observation that nearly l % of those aged 30+ years are dying annually from unrecognized cardiovascular disease has led to a proposed assessment of Holter (ambulatory ECG) monitoring for the detection of silent myocardial ischemia. In this way, we will identify risk factors responsible for complications enabling the development of appropriate preventive strategies.